Abstract
In Alzheimer’s disease and related tauopathies, trans-synaptic transfer and accumulation of pathological tau from donor to recipient neurons is thought to contribute to disease progression, but the underlying mechanisms are poorly understood. Using complementary in vivo and in vitro models, we examined the relationship between these two processes and neuronal clearance. Accumulation of p62 (a marker of defective protein clearance) correlated with pathological tau accumulation in two mouse models of tauopathy spread; Entorhinal Cortex-tau (EC-Tau) mice where tau pathology progresses in time from EC to other brain regions, and PS19 mice injected with tau seeds. In both models and in several brain regions, p62 colocalized with human tau in a pathological conformation (MC1 antibody). In EC-Tau mice, p62 accumulated before overt tau pathology had developed and was associated with the presence of aggregation-competent tau seeds identified using a FRET-based assay. Furthermore, p62 accumulated in the cytoplasm of neurons in the dentate gyrus of EC-Tau mice prior to the appearance of MC1 positive tauopathy. However, MC1 positive tau was shown to be present at the synapse and to colocalize with p62 as shown by immuno electron microscopy. In vitro, p62 colocalized with tau inclusions in two primary cortical neuron models of tau pathology. In a three-chamber microfluidic device containing neurons overexpressing fluorescent tau, seeding of tau in the donor chamber led to tau pathology spread and p62 accumulation in both the donor and the recipient chamber. Overall, these data are in accordance with the hypothesis that the accumulation and trans-synaptic spread of pathological tau disrupts clearance mechanisms, preceding the appearance of obvious tau aggregation. A vicious cycle of tau accumulation and clearance deficit would be expected to feed-forward and exacerbate disease progression across neuronal circuits in human tauopathies.
Highlights
IntroductionNeurodegenerative diseases are characterized by the accumulation of pathological neurotoxic proteins within neurons and/or glia [64]
Despite their clinical heterogeneity, neurodegenerative diseases are characterized by the accumulation of pathological neurotoxic proteins within neurons and/or glia [64]
Clearance dysfunction is associated with propagated tau pathology in vivo To model tau spread in PS19 mice which express human tau with the P301S mutation [77], tau seeds were inoculated into the hippocampal dentate gyrus (DG) and left for 30 days
Summary
Neurodegenerative diseases are characterized by the accumulation of pathological neurotoxic proteins within neurons and/or glia [64]. One hypothesis is that specific brain regions, or classes of neuron [24, 25] have differing intrinsic susceptibility to the development of tau pathology [71], with some structures affected earlier and others later in the disease. One approach involves the injection of pathological tau seeds from different sources into the brains of tau transgenic or wildtype (WT) mice, which leads to enhanced or de novo pathology respectively, first at the injection locus, and later in remote, but connected regions [7, 8, 12, 29, 36, 39, 53]. The hypothesis that the spread of tauopathy between neurons could be mediated by the passage of tau seeds across the extracellular space was inferred from in vivo studies [6, 19] and strengthened by in vitro studies using neurons that were engineered to develop tau pathology or stimulated to do so by the addition of exogenous tau seeds [5, 12, 68, 75]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
